Rotator cuff tears affect 40% or more of those over age 60 and cost the US economy approximately $3 billion per year. As many as 90% of large rotator cuff tears that are repaired re-tear, resulting in long-term shoulder disability. High re-tear rates following rotator cuff repair depend on mechanical factors and biologic factors that may compromise the patients' intrinsic capacity to heal. Hence, there is a critical need for repair strategies that provide adequate strength as well as stimulate and enhance the patients' healing potential. The long-term goal of our research program is to design effective strategies for successful repair of large, chronic rotator cuff tears. The objective of this application is to establish the extent to which fascia extracellular matrix (ECM), engineered with and without biologic enhancement, can improve the functional outcomes of rotator cuff repair. Our central hypothesis is that biologic enrichment enhances the host response to fascia such that augmenting rotator cuff repairs with engineered fascia will improve repair outcomes over conventional suture only repair or augmentation with native fascia. Our rationale is to provide the orthopaedic surgeon with a mechanically robust, natural scaffold that will foster functional tendon-bone bridging and thereby improve outcomes in rotator cuff repair patients. The specific aims of this project are to 1) identify the biologic treatment level that maximizes cell infiltration into fascia ECM 2) reduce chronic inflammation associated with fascia ECM, 3) improve rotator cuff repair outcomes using fascia ECM. The experimental approach will be to investigate tenocyte infiltration into engineered fascia using an in vitro cell culture model, in order to establish the treatment that maximizes cell infiltration into the ECM. Subsequently, the ability of engineered fascia to modulate chronic inflammation, as defined by the number of persisting lymphocytes and plasma cells, will be quantified in a rat abdominal wall defect model. Finally, the ability of engineered fascia ECM to improve outcomes in a large animal rotator cuff injury and repair model will be investigated. At the conclusion of this work, we expect to have developed a novel strategy for rotator cuff repair--engineered fascia ECM-- that is both mechanically suitable and biologically beneficial. By ultimately assessing the ability of our approach to enhance rotator cuff repair outcomes in a relevant, pre-clinical, animal model, judgments regarding the translation of this repair strategy to human patients can be made. Importantly, these studies will also provide the foundational paradigm for evaluating any number of modified or alternate therapeutic approaches to rotator cuff repair. Strategies to successfully treat patients with large, chronic rotator cuff tears will dramatically reduce the incidence of debilitating pain, reduced shoulder function and weakness that chronically plague many elderly individuals, instead allowing them to maintain a healthy, active lifestyle in later years. PUBLIC HEALTH RELEVANCE. Rotator cuff injuries affect approximately 30-40% of the population over age 60 and have a major impact on the cost of medical care and the number of days lost from work. The proposed research will provide the shoulder surgeon with a natural, strong, regenerative scaffold for rotator cuff repair. Strategies to successfully treat patients with large, chronic rotator cuff tears will dramatically reduce the incidence of debilitating pain, reduced shoulder function and weakness that chronically plague many elderly individuals, instead allowing them to maintain a healthy, active lifestyle in later years.